According to ICH Q8 guidelines, the biopharmaceutical manufacturer submits a design space (DS) definition as part of the regulatory approval application, in which case process parameter (PP) deviations within this space are not considered a change and do not trigger a regulatory post approval procedure. A DS can be described by non-linear PP ranges, i.e., the range of one PP conditioned on specific values of another. However, independent PP ranges (linear combinations) are often preferred in biopharmaceutical manufacturing due to their operation simplicity. While some statistical software supports the calculation of a DS comprised of linear combinations, such methods are generally based on discretizing the parameter space - an approach that scales poorly as the number of PPs increases. Here, we introduce a novel method for finding linear PP combinations using a numeric optimizer to calculate the largest design space within the parameter space that results in critical quality attribute (CQA) boundaries within acceptance criteria, predicted by a regression model. A precomputed approximation of tolerance intervals is used in inequality constraints to facilitate fast evaluations of this boundary using a single matrix multiplication. Correctness of the method was validated against different ground truths with known design spaces. Compared to stateof-the-art, grid-based approaches, the optimizer-based procedure is more accurate, generally yields a larger DS and enables the calculation in higher dimensions. Furthermore, a proposed weighting scheme can be used to favor certain PPs over others and therefore enabling a more dynamic approach to DS definition and exploration. The increased PP ranges of the larger DS provide greater operational flexibility for biopharmaceutical manufacturers.
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In this paper, we investigate the two-dimensional extension of a recently introduced set of shallow water models based on a regularized moment expansion of the incompressible Navier-Stokes equations \cite{kowalski2017moment,koellermeier2020analysis}. We show the rotational invariance of the proposed moment models with two different approaches. The first proof involves the split of the coefficient matrix into the conservative and non-conservative parts and prove the rotational invariance for each part, while the second one relies on the special block structure of the coefficient matrices. With the aid of rotational invariance, the analysis of the hyperbolicity for the moment model in 2D is reduced to the real diagonalizability of the coefficient matrix in 1D. Then we prove the real diagonalizability by deriving the analytical form of the characteristic polynomial. Furthermore, we extend the model to include a more general class of closure relations than the original model and establish that this set of general closure relations retain both rotational invariance and hyperbolicity.
We introduce a transformation framework that can be utilized to develop online algorithms with low $\epsilon$-approximate regret in the random-order model from offline approximation algorithms. We first give a general reduction theorem that transforms an offline approximation algorithm with low average sensitivity to an online algorithm with low $\epsilon$-approximate regret. We then demonstrate that offline approximation algorithms can be transformed into a low-sensitivity version using a coreset construction method. To showcase the versatility of our approach, we apply it to various problems, including online $(k,z)$-clustering, online matrix approximation, and online regression, and successfully achieve polylogarithmic $\epsilon$-approximate regret for each problem. Moreover, we show that in all three cases, our algorithm also enjoys low inconsistency, which may be desired in some online applications.
Consider the problem of determining the effect of a compound on a specific cell type. To answer this question, researchers traditionally need to run an experiment applying the drug of interest to that cell type. This approach is not scalable: given a large number of different actions (compounds) and a large number of different contexts (cell types), it is infeasible to run an experiment for every action-context pair. In such cases, one would ideally like to predict the outcome for every pair while only having to perform experiments on a small subset of pairs. This task, which we label "causal imputation", is a generalization of the causal transportability problem. To address this challenge, we extend the recently introduced synthetic interventions (SI) estimator to handle more general data sparsity patterns. We prove that, under a latent factor model, our estimator provides valid estimates for the causal imputation task. We motivate this model by establishing a connection to the linear structural causal model literature. Finally, we consider the prominent CMAP dataset in predicting the effects of compounds on gene expression across cell types. We find that our estimator outperforms standard baselines, thus confirming its utility in biological applications.
Persistence modules stratify their underlying parameter space, a quality that make persistence modules amenable to study via invariants of stratified spaces. In this article, we extend a result previously known only for one-parameter persistence modules to grid multi-parameter persistence modules. Namely, we show the $K$-theory of grid multi-parameter persistence modules is additive over strata. This is true for both standard monotone multi-parameter persistence as well as multi-parameter notions of zig-zag persistence. We compare our calculations for the specific group $K_0$ with the recent work of Botnan, Oppermann, and Oudot, highlighting and explaining the differences between our results through an explicit projection map between computed groups.
In this paper, we study the estimation of the derivative of a regression function in a standard univariate regression model. The estimators are defined either by derivating nonparametric least-squares estimators of the regression function or by estimating the projection of the derivative. We prove two simple risk bounds allowing to compare our estimators. More elaborate bounds under a stability assumption are then provided. Bases and spaces on which we can illustrate our assumptions and first results are both of compact or non compact type, and we discuss the rates reached by our estimators. They turn out to be optimal in the compact case. Lastly, we propose a model selection procedure and prove the associated risk bound. To consider bases with a non compact support makes the problem difficult.
Finite element methods and kinematically coupled schemes that decouple the fluid velocity and structure's displacement have been extensively studied for incompressible fluid-structure interaction (FSI) over the past decade. While these methods are known to be stable and easy to implement, optimal error analysis has remained challenging. Previous work has primarily relied on the classical elliptic projection technique, which is only suitable for parabolic problems and does not lead to optimal convergence of numerical solutions to the FSI problems in the standard $L^2$ norm. In this article, we propose a new kinematically coupled scheme for incompressible FSI thin-structure model and establish a new framework for the numerical analysis of FSI problems in terms of a newly introduced coupled non-stationary Ritz projection, which allows us to prove the optimal-order convergence of the proposed method in the $L^2$ norm. The methodology presented in this article is also applicable to numerous other FSI models and serves as a fundamental tool for advancing research in this field.
Automated program repair techniques aim to aid software developers with the challenging task of fixing bugs. In heuristic-based program repair, a search space of program variants is created by applying mutation operations on the source code to find potential patches for bugs. Most commonly, every selection of a mutation operator during search is performed uniformly at random. The inefficiency of this critical step in the search creates many variants that do not compile or break intended functionality, wasting considerable resources as a result. In this paper, we address this issue and propose a reinforcement learning-based approach to optimise the selection of mutation operators in heuristic-based program repair. Our solution is programming language, granularity-level, and search strategy agnostic and allows for easy augmentation into existing heuristic-based repair tools. We conduct extensive experimentation on four operator selection techniques, two reward types, two credit assignment strategies, two integration methods, and three sets of mutation operators using 22,300 independent repair attempts. We evaluate our approach on 353 real-world bugs from the Defects4J benchmark. Results show that the epsilon-greedy multi-armed bandit algorithm with average credit assignment is best for mutation operator selection. Our approach exhibits a 17.3% improvement upon the baseline, by generating patches for 9 additional bugs for a total of 61 patched bugs in the Defects4J benchmark.
The usability of Reinforcement Learning is restricted by the large computation times it requires. Curriculum Reinforcement Learning speeds up learning by defining a helpful order in which an agent encounters tasks, i.e. from simple to hard. Curricula based on Absolute Learning Progress (ALP) have proven successful in different environments, but waste computation on repeating already learned behaviour in new tasks. We solve this problem by introducing a new regularization method based on Self-Paced (Deep) Learning, called Self-Paced Absolute Learning Progress (SPALP). We evaluate our method in three different environments. Our method achieves performance comparable to original ALP in all cases, and reaches it quicker than ALP in two of them. We illustrate possibilities to further improve the efficiency and performance of SPALP.
Context: Software development benefits from having Boundary Artefacts (BAs), as a single artefact can supply stakeholders with different boundaries, facilitating collaboration among social worlds. When those artefacts display inconsistencies, such as incorrect information, the practitioners have decreased trust in the BA. As trust is an essential factor guiding the utilisation of BAs in software projects, it is necessary to understand which principles should be observed when creating them. Objective: This study aimed at develop and validate a preliminary guideline support the creation of trustworthy BAs. Method: We followed a multi-step approach. We developed our guideline through a literature review and previous results from our case study. Second, we submitted the guideline for an expert evaluation via two workshops and a survey. At last, we adjusted our guideline by incorporating the feedback obtained during the workshops. Results: We grouped the principles collected from a literature review into three categories. The first category (Scope) focuses on the scope, displaying principles referring to defining each boundary's target audience, needs, and terminology. The second category (Structure) relates to how the artefact's content is structured to meet stakeholders' needs. The third (Management) refers to principles that can guide the establishment of practices to manage the artefact throughout time. The expert validation revealed that the principles contribute to creating trustworthy BAs at different levels. Also, the relevance of the guideline and its usefulness. Conclusions: The guideline strengthen BA traits such as shared understanding, plasticity and ability to transfer. Practitioners can utilise the guideline to guide the creation or even evaluate current practices for existing BAs.
In this paper, we propose a novel, computationally efficient reduced order method to solve linear parabolic inverse source problems. Our approach provides accurate numerical solutions without relying on specific training data. The forward solution is constructed using a Krylov sequence, while the source term is recovered via the conjugate gradient (CG) method. Under a weak regularity assumption on the solution of the parabolic partial differential equations (PDEs), we establish convergence of the forward solution and provide a rigorous error estimate for our method. Numerical results demonstrate that our approach offers substantial computational savings compared to the traditional finite element method (FEM) and retains equivalent accuracy.
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